Epidermal growth factor receptor-mediated motility in fibroblasts

Cell motility is induced by many growth factors acting through cognate rece ptors with intrinsic tyrosine kinase activity (RPTK). However, most of the links between receptor activation and the biophysical processes of cell mot ility remain undeciphered. We have focused on the mechanisms by which the E GF receptor (EGFR) actuates fibroblast cell motility in an attempt to defin e this integrated process in one system. Our working model is that divergen t, but interconnected pathways lead to the biophysical processes necessary for cell motility: cytoskeleton reorganization, membrane extension, formati on of new adhesions to substratum, cell contraction, and release of adhesio ns at the rear. We postulate that for any given growth factor some of the p athways/processes will be actively signaled and rate-limiting, while others will be permissive due to background low-level activation. Certain couplin gs have been defined, such as PLC gamma and actin modifying proteins being involved in cytoskeletal reorganization and lamellipod extension and MEK be ing implicated in detachment from substratum. Others are suggested by compl ementary investigations in integrin-mediated motility, including rac in mem brane protrusion, rho in new adhesions, myosin II motors in contraction, an d calpain in detachment, but have yet to be placed in growth factor-induced motility. Our model postulates that many biochemical pathways will be shar ed between chemokinetic and haptokinetic motility but that select pathways will be activated only during RPTK-enhanced motility. (C) 1998 Wiley-Liss, Inc.